This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. AIMS: Monoamine transporters regulate neurotransmitter levels, which release or sequester them from and into neurons. Cocaine and other psychostimulants inhibit the dopamine (DAT) and norepinephrine (NET) transporters, with relative potencies that correlate with their potencies for producing stimulant effects and abuse liability. The trace amine phenylethylamine (PEA) is implicated in addiction, but the relationship between PEA, monoamine transporters and drugs is unknown. We postulated that PEA is a substrate for the DAT and NET, that drugs would potently inhibit [3H]PEA transport and that blockade of (3H)PEA transport by DAT inhibitors would be relevant to the stimulant and reinforcing properties of cocaine-like drugs. METHODS: We measured (3H)PEA transport kinetics, compared drug effects on (3H)PEA and (3H)dopamine transport in human DAT-HEK-293 cells, and compared relative drug potencies in vitro with reported drug potencies for producing behavioral effects in primates. RESULTS: (3H)PEA was actively transported, with DAT and NET affinities similar to (3H)dopamine or (3H)norepinephrine affinities. (-)-Cocaine and other drugs dose-dependently inhibited PEA transport by the DAT, at greater potencies than those that block (3H)dopamine transport. The relative potencies of drugs for blocking (3H)PEA transport correlated highly with their reported relative potencies for producing psychomotor stimulation and maintaining self-administration in primates. CONCLUSIONS: Drug inhibition of PEA transport by the DAT and NET conceivably elevates extracellular PEA levels in brain. These results implicate PEA and the trace amine receptor1 activation as contributors to the psychostimulant and reinforcing effects of DAT inhibitors.